The goal of modern oligosaccharide synthesis is the efficient production of natural and unnatural oligosaccharides, and their mimetics, capable of interfering constructively in disease states. This interference may be brought about by the blocking of oligosaccharide processing enzymes, by disruption of bacterial cell wall biosynthesis, by modulating cell-cell recognition, by enhancing binding and selectivity of drugs to DNA, and by the provision of antigenic oligosaccharides in synthetic vaccines. All of these very desirable processes require the highly efficient synthesis of oligosaccharides. Ultimately it is to be hoped that oligosaccharide synthesis can be developed to a point at which programmable, automated solid phase synthesis is a real possibility. Although oligosaccharide synthesis has developed in leaps and bounds in the last decade or so, this goal is still a long way off. The reasons for this are multiple and reside in the complexity of the chemistry of formation of glycosidic bonds. An absolutely overwhelming number of methods toward this end have been devised, however, the vast majority of these have been developed empirically and they are therefore underpinned by very little detailed understanding of mechanism. The main thesis of this proposal is that the ultimate goal of automated oligosaccharide synthesis demands a simplification of the area and that this simplification can best be brought about by a detailed investigation of the mechanisms of a few of the more successful glycosylation reactions. It is hoped that such careful investigations will shed new light on the true nature of glycosylating species and so help standardize methods and conditions. Toward this end a series of investigations are proposed into the mechanism of several important classes of glycosylation reaction, namely the thioglycoside method with the formation of intermediate glycosyl triflates, the activation of thioglycosides by means of N-iodosuccinimide, and the trichloroacetimidate method. These studies will involve characterization of the actual intermediates following activation, and determination of the molecularity of the actual coupling processes by measurement of secondary alpha-deuterium kinetic isotope effects. Neighboring group participation is of critical importance for controlling stereochemistry in many types of glycosylation, but its understanding lags far behind its level of application. In particular we will focus on neighboring group participation by esters at the 3-position, both in terms of the use of this effect in alpha-glucosylation and the like, and in terms of preventing this participation yet retaining the powerful disarming ability of an ester at the 3-position. We will also undertake a study of N-acetylneuraminic acid chemistry with the two fold intention of developing improved stereoselective glycosylation protocols for the formation of alpha-sialyl glycosides, and of improving the reactivity of sialic acid derivatives as glycosyl acceptors.